Benzoyl peroxide is used extensively in dermatologic pharmaceutical compositions. Many compositions for the treatment of acne vulgaris and acne rosacea, for example, contain between 2.5% and 10% benzoyl peroxide. The effectiveness of benzoyl peroxide in treating these and other dermatologic conditions is in its usefulness as a keratolytic agent, thereby increasing skin turnover and clearing pores. Benzoyl peroxide additionally has direct antibacterial activity.
A serious difficulty in obtaining stable dispersions of benzoyl peroxide in aqueous fluids is that benzoyl peroxide is a highly hydrophobic organic compound and is not readily wetted by water. This problem has been dealt with by the prior art in one or more ways.
Benzoyl peroxide may be dissolved in an organic solvent, thus avoiding the problem of preparing a stable, homogeneous, cosmetically elegant and efficacious dispersion of benzoyl peroxide for topical administration for treating a skin affliction. Early products containing benzoyl peroxide in solution for topical use were gels in which the benzoyl peroxide was dissolved in an organic solvent such as acetone or a combination of alcohol and acetone. These products proved to be efficacious, however they suffered from several disadvantages including flammability, over-drying the skin, and causing skin irritation in many acne sufferers. More recent developments have used other organic solvents to solubilize benzoyl peroxide. However these compositions do not solve the problem of severe skin irritation in a significant number of subjects due to the problem of bolus delivery of solubilized benzoyl peroxide into the pilo-sebaceous apparatus of the skin.
For these and other reasons, including increased production of degradation products that occurs with solutions, suspensions of benzoyl peroxide are preferred over solutions. Micro-suspensions, which are suspensions containing micronized benzoyl peroxide, are preferred to standard or non-micronized suspensions of benzoyl peroxide for several reasons, including the following exemplary reasons. First, micronized suspensions provide effective delivery of small particles of benzoyl peroxide into the infundibulum of the pilo-sebaceous apparatus, in which they lodge and from which they provide non-bolus delivery of drug into the sebum and pilo-sebaceous tissue. This delivery provides a proper balance of optimal efficacy and reduction of skin irritation reactions. Second, cosmetic elegance and patient acceptance are improved with the smooth, homogeneous gels, creams or lotions containing suspended finely divided or micronized benzoyl peroxide, rather than dissolved benzoyl peroxide which requires significant amounts of organic solvents. Particularly in treating facial conditions of the skin such as acne or acne rosacea, cosmetic elegance is an important factor in obtaining good patient compliance with treatment instructions. For chronic diseases with ongoing topical drug management, good patient compliance is essential in obtaining overall treatment success.
Surfactants are often utilized as wetting agents to help disperse benzoyl peroxide in aqueous fluids and to maintain benzoyl peroxide in suspension during processing and in the finished formulation. Surfactants, however, are often irritating to damaged or diseased skin and, when applied to intact skin repeatedly, surfactants are known to disrupt the normal skin barrier function as evidenced by an increase in trans-epidermal water loss from the skin. Therefore it is desirable to formulate pharmaceutical compositions, particularly those that will be used daily over extended periods for treating chronic skin conditions, with minimal or no surfactants. In order to facilitate dispersion of benzoyl peroxide and to maintain the dispersion of benzoyl peroxide in suspension, a micronized form of benzoyl peroxide is often utilized, sometimes in conjunction with a surfactant.
Cox, U.S. Pat. No. 3,535,422, discloses a stable emulsion containing benzoyl peroxide. Cox discloses two methods to obtain the emulsion containing benzoyl peroxide in suspension. In a first method, Cox forms an emulsion containing water, a surfactant, and up to 25% of a saturated organic compound emollient. Dry micronized benzoyl peroxide is then blended into this emulsion to obtain the composition. In a second method, utilizing non-micronized benzoyl peroxide, coarse crystals of benzoyl peroxide in the form of a powder packaged wet with water are combined with a previously made emulsion containing all of the components of the composition, including a surfactant and a saturated organic compound emollient. The resulting composition is then milled in order to obtain a composition containing micronized benzoyl peroxide.
Young, U.S. Pat. No. 4,056,611, discloses a single-phase composition containing benzoyl peroxide in suspension. The composition of Young contains an alcoholic solvent, water, and a surfactant as necessary components. Like Cox, Young discloses that the composition may be made by using dry micronized benzoyl peroxide crystals. Preferably, Young utilizes, as does Cox, a wet-packed powder of coarse crystals of benzoyl peroxide, which powder contains about 70% benzoyl peroxide and 30% w/w water. All of the components of the composition are mixed together and then this mixture is milled to obtain a composition containing micronized benzoyl peroxide in suspension. Young further discloses that the compositions may advantageously contain a suspending agent to maintain the benzoyl peroxide particles in suspension and a viscosity building (gelling) agent.
The Cox and Young methods and compositions contain several disadvantages pertaining to compositions containing benzoyl peroxide. In both Cox and Young, surfactants are utilized, which are often irritating to damaged or diseased skin. Further, both Cox and Young disclose combining together all constituents of their compositions containing coarse, non-micronized benzoyl peroxide to form a mixture and then milling this mixture to obtain a composition containing micronized benzoyl peroxide. Although Young discloses that a gelling agent may be combined in the composition, it is well known that the mechanical milling forces used to micronize benzoyl peroxide will likewise tend to disrupt the polymers utilized as gelling agents. Thus, the milling process results in a reduction of the ability of the gelling agents to provide the viscosity that is desired.
Klein, U.S. Pat. No. 4,387,107, discloses gel compositions containing benzoyl peroxide. Klein avoids the problem of milling a composition containing benzoyl peroxide by using benzoyl peroxide that is pre-micronized prior to combining with the remaining ingredients. In order to make the composition of Klein, water is combined with a gelling agent to make a first mixture. To this mixture is optionally added an alcohol vehicle and other components such as a perfume and other therapeutic agents such as methyl salicylate. Finally, a second mixture containing micronized benzoyl peroxide, a surfactant, and water is added to the first mixture to obtain the composition. Because micronized benzoyl peroxide is used, there is no need to mechanically mill the composition. Thus, the polymeric gelling agents are not disrupted. However, the method of Klein requires the use of pre-micronized benzoyl peroxide and the presence of a surfactant.
The use of micronized benzoyl peroxide, as disclosed in Klein, provides advantages, particularly regarding the formation of semi-solid compositions containing one or more polymeric gelling agents. Micronized, as opposed to non-micronized benzoyl peroxide, is more readily suspended in a hydrophilic fluid and such suspensions are more physically stable than are similar suspensions made with non-micronized benzoyl peroxide. However, micronized benzoyl peroxide, particularly as pharmaceutical grade material, is often difficult to obtain and, when it is obtainable, micronized benzoyl peroxide is expensive.
It would, therefore, be advantageous to be able to purchase non-micronized benzoyl peroxide, which is readily available and is much less expensive than micronized benzoyl peroxide, and to then be able to micronize the benzoyl peroxide for use in manufacturing pharmaceutical formulations.
As disclosed in both the Cox and Young patents, benzoyl peroxide, in solid crystalline form, is stable at room temperature but is flammable and capable of exploding when subjected to temperatures associated with grinding. Consequently, dry milling of benzoyl peroxide is not preferred. Rather, it is preferred to wet-mill benzoyl peroxide in order to obtain benzoyl peroxide in a micronized form. Benzoyl peroxide in the presence of water, which is utilized in the preferred wet milling processes, is much safer to process as the risk of fire and explosion is minimized.
Baroody, U.S. Pat. No. 6,117,843, discloses in Example 8 the making of a benzoyl peroxide suspension in an aqueous medium. According to the method of Baroody, propylene glycol was dissolved in water and then a carboxy vinyl polymer was added, followed by addition of a neutralizing agent to obtain a dispersion having a desired pH. Then, benzoyl peroxide was levigated with a portion of the carboxy vinyl polymer dispersion and passed through a homogenizer until the average particle size was less than 25 microns in diameter. Finally, this benzoyl peroxide dispersion was combined with additional water and mixed until a homogenous suspension was obtained.
The method disclosed in Baroody utilizes polymer in order to build significant viscosity and thereby facilitate a high energy mechanical process of wetting. The aqueous fluid to which the BPO is added is a gel. The gel provides thickening, suspending, and coating properties for the BPO powder, which is levigated in a portion of the carboxy vinyl polymer dispersion in order to make the suspension. There are several disadvantages associated with the method of Baroody. One such disadvantage is that the milling process that is part of the method may lead to breakdown of the polymer that is within the dispersion with subsequent loss of gel viscosity and/or stability. Another disadvantage with the Baroody method is that levigation is a manual mechanical laboratory procedure and is not readily translatable to scaled-up commercial manufacture.
One difficulty encountered in wet-milling benzoyl peroxide, as mentioned above, is that benzoyl peroxide is highly hydrophobic and resists wetting with water. Further, the strong attractive forces between benzoyl peroxide particles create a problem of aggregation which may compromise both the manufacturing process and the quality of the final pharmaceutical formulation. Surfactants have been utilized for this purpose and to maintain a stable-non-agglomerated micro-suspension of benzoyl peroxide, as disclosed in each of Cox, Young, and Klein patents, but surfactants are not preferred due to their tendency to irritate sensitive, damaged, or diseased skin. Therefore, a method in which benzoyl peroxide may be readily wetted, and preferably placed into a stable suspension, in a hydrophilic or aqueous fluid, and preferably without the use of surfactants, would be of great benefit.